The overall goals of this K24 award are to 1) contribute to our understanding of the etiology and prevention of digestive diseases through patient-oriented research (POR) that synthesizes rigorous epidemiological methods with novel molecular correlates of disease; 2) educate and mentor the next generation of clinician investigators in gastroenterology (GI). The principal investigator (PI), a leading clinical researcher in GI, has an established track record of mentoring fellows and junior faculty within the outstanding research and training environment of the Massachusetts General Hospital (MGH) GI Unit, the Harvard School of Public Health (HSPH), and the Channing Laboratory, which each offer access to motivated and talented trainees. Many of the PI's trainees have successfully secured their own career development awards and collectively have been lead authors on 17 publications in high-impact journals. The PI's outstanding institutional support, access to core resources, and successful and well-funded research portfolio has facilitated his mentoring activities and will be sustained over the time period of the award. The PI's career development objectives are as follows: 1) sustain and expand a POR program in colorectal cancer (CRC) and inflammatory bowel disease (IBD) to provide opportunities for trainees to conduct high impact POR that will enable them to launch independent careers; 2) implement a highly structured, individualized, and competency-based mentoring plan to maximize trainee research productivity and prepare for careers in POR; 3) become a more effective mentor through didactic training; 4) develop new skills in the analysis and interpretation of high-dimensional data; 5) assume local and national leadership in programmatic efforts to systematically improve mentoring of early POR investigators. To achieve these goals, the PI will offer mentored research studies for trainees which draws upon diverse study designs and data, including: 1) analytic epidemiological studies to identify lifestyle or environmental determinants of disease; 2) investigation of these lifestyle factors in the context of molecular biomarkers to better elucidate their role in the disease pathogenesis; 3) validation of these findings within intervention studies to further establish causality. As examples of this approach, the PI will mentor fellows and junior faculty in POR investigations of the role of inflammation in colorectal neoplasia and vitamin D in IBD. These hypothesis-based studies will provide fresh insights into the potential mechanisms involved in CRC and IBD pathogenesis and strategies for risk modification for individuals at high risk. Moreover, this research offers rich opportunities for junior investigators to be mentored within the full continuum of clinical and molecular epidemiological investigation. The PIs research infrastructure will allow rapid and efficient exploration of future hypotheses related to lifestyle, biochemical, and genetic risk factors for CRC and IBD that can serve as a platform for additional trainee projects and career award applications, thereby facilitating the emergence of the PI's trainees as the next generation of independent clinical investigators.